HU190044B - Process for producing 2/-fluoro-alkyl-thio/-substituted-peneme-carboxylic acid derivatives - Google Patents

Abstract

Disclosed herein are (5R,6S,8R)-6-(1-hydroxyethyl)-2-(2-fluoroethylthio)-penem-3-carboxylic acid and the metabolisable esters thereof and alkali metal salts thereof, which are potent antibacterial agents.

Description

The present invention relates to a process for the preparation of 6- (1-hydroxyethyl) -2- (fluoro-lower alkylthiol-pentemecarboxylic acid derivatives, their pharmaceutically acceptable salts, pivaloyloxymethyl esters and pharmaceutical compositions containing them).

U.S. Patent Nos. 4,260,618,4,301,074, Japanese Patent Nos. 55-153789 and British Patent 2,013,674 disclose 2-substituted penem derivatives.

The compounds of the invention are represented by Formula I - wherein the stereochemistry is 5R, 6S.8R or 5R, 6R, 8S,

C2-C4 linear or branched fluoroalkyl having from 1 to 3 fluorine atoms on carbon at least one carbon atom separated from position 2 of the sulfur atom, and

R is hydrogen, a pharmaceutically acceptable cation or a pivaloyloxymethyl group.

The preferred configuration is 5R, 6S, 8R. Preferably R is potassium or sodium.

Straight fluoroalkyl groups are derivatives of ethyl, n-propyl and n-butyl groups, with fluoroethyl groups being preferred. Thus, the most preferred compound is the sodium or potassium salt of (5R, 6S, 8R) -2- (2'-fluoroethylthio) -6- (1-hydroxyethyl) -penem-3-carboxylic acid.

Branched fluoroalkyl groups are derivatives of isopropyl, sec-butyl and tert-butyl groups. The chain may be branched on a carbon atom attached to the sulfur atom or on a second carbon atom from the sulfur atom.

Preferred branched-chain fluoroalkyl groups

-CH ₂ -CH-F and -CH-CH ₂ F wherein R 'is methylR R or ethyl; and -SCH-CHF. Other typical representations of substitution A subchapter ₃ ch _{3 are} -CH ₂ CF ₃ , ch ₃

-CH ₂ CH ₂ CF _3; and -CH ₂ CHCF ₃ .

The pharmaceutically acceptable cations mentioned above are alkali metal cations such as sodium and potassium, alkaline earth metal cations such as calcium and quaternary ammonium cations such as Ν-methylglucamine, pyridinium, triethylammonium. or triethanolammonium cations. Sodium and potassium salts are preferred.

The 2-monofluoroalkylthio derivatives of the formula I are represented by the compound of the formula II, in which the stereochemistry Z is a linear or branched C 2 -C 4 alkyl group substituted by a Lg group which can be replaced by a fluorine atom under the reaction conditions. is separated from the 2-sulfur atom by at least 2 carbon atoms, X is a carboxyl protecting group and, if necessary, the 8-position hydroxy group of the penem molecule is protected by fluorination and optionally removing the protecting group (s) present or by preparing an acceptable salt or pivaloyloxymethyl ester.

The Lg group may be, for example, hydroxyl, trifluoromethylsulfonyl. trichloromethylsulfonyl, arylsulfonyl and alkyl. an ulphonyl group or a bromine or iodine atom. The hydroxy group h is preferred.

Fluorination is generally accomplished by reacting a compound of formula II with a suitable fluorinating agent in an inert solvent without a hydroxyl group. The pH is generally between 4 and 8.

The preferred fluorinating agent is diethylamino sulfur trifluoride (PAST). Other suitable fluorinating agents are, for example, potassium fluoride, a compound of the formula R ₄ ⁺ NF ', wherein R is, for example, an aryl or alkyl group, sulfur tetrafluoride or a group of the formula (a) wherein R is as defined above. Suitable inert solvents include dichloromethane, trichloromethane and hexanes.

The fluorination reaction proceeds at room temperature to -70 ° C. The preferred temperature range is from 25 ° C to -20 ° C.

When the leaving group Lg is not a hydroxy group, fluorinating agents include R ₄ ⁺ NF 'and potassium fluoride. In these cases, it is preferable that the 8-hydroxy group is unprotected.

The intermediates of formula II wherein Lg is a hydroxy group are preferably prepared by stereospecific synthesis as described in European Patent Application Publication No. 0058317. Intermediates of Formula II wherein Lg is other than hydroxy are prepared, if necessary, from compounds of Formula II wherein Lg is hydroxy, starting from the appropriate materials and employing conventional esterification techniques. The chiral intermediate, methyl 5R, 6S, 8R or 5R, 6R, 8S / -2,2-dimethyl-6- / 1-trichloroethoxycarbonyloxyethyl / penam-3-carboxylate, is known in the art. , may be prepared by the procedure described in European Patent Application Publication No. 0013662.

Another process for the preparation of compounds of formula I is a compound of formula IIIa IIIb, in which the stereochemistry 5R, 6S, 8R or 5R, 6R, 8S, X is a carboxyl protecting group and the 8-hydroxy group is optionally protected, wherein G is a C2-C4 straight or branched alkyl group and has one to three fluorine atoms per carbon atom, which is separated by at least one carbon atom from the Y atom or group, and Y is a leaving group under reaction conditions. alkylation and deprotection and isolation of the penem reaction product in the form of a free acid, a pharmaceutically acceptable salt, or a metabolizable ester thereof.

Intermediates IIIa and IIIb may be prepared as described in Japanese Patent Publication No. 74762/1980. Accordingly, a compound of formula V, wherein R is a protected 1-hydroxyethyl group, Rg is a lower alkyl group, and X is a carboxy protecting group, is reacted with carbon disulfide.

Reaction with -2190 044 zis such as lithium hexamethyldisilazane followed by reaction with phosgene affords a compound of formula VI which is then halogenated, for example with chlorine or sulfuryl chloride, to give a compound of formula VII wherein Hal is halogen. The ring closure of the compound of formula VII in the presence of a base such as methylamine or ethylamine gives the tautomeric compound of formula VIIIaIIb. Generally, even starting from stereospecific intermediates, the tautomeric product (Villa, VIIIb) is a mixture of diastereomers. For the 5S isomers, the isomerization procedure described in Tetrahedron Letters (22, 3485) and / or, if necessary, conventional separation techniques such as chromatographic separation, fractional crystallization, can be used to separate substantially pure enantiomers (IXa, IXb) of the desired stereochemistry.

The 8-hydroxy protecting group may be removed before or after resolution of the desired enantiomer, if desired.

Alkylation of the compounds of formula VIIIa, VIIIb is generally carried out with a compound of formula IV wherein Y is a chlorine, bromine or iodine group or an alkylsulfonyloxy or arylsulfonyloxy group. The reaction is usually carried out in an inert organic solvent in the presence of a base such as tetrahydrofuran or a halogenated hydrocarbon such as chloroform in the presence of an organic base such as pyridine or an alkali metal carbonate such as potassium carbonate. Suitable alkylation temperatures range from -10 ° C to 100 ° C.

A further process for the preparation of compounds of Formula I is a compound of Formula X, wherein the stereochemistry is 3S, 4R, 5R or 3R, 4R, 5S, A fluoroalkyl which is a straight or branched chain carbon atom separated from the sulfur atom by at least one carbon atom. Contains 1 to 3 fluorine atoms, X is a carboxyl protecting group and optionally the 5-position hydroxyl is protected - and a trivalent organic phosphorus compound such as triethyl phosphite or triphenylphosphite followed by removal of the protecting group (s) and free penem in the form of an acid, a pharmaceutically acceptable salt or a pivaloyloxymethyl ester.

The intermediate of formula X can be prepared and further elaborated according to the method described in European Patent Publication No. 0058317.

Thus, the intermediate of Formula X is an azetidinone of Formula XI, wherein A is as defined above in an inert solvent of formula (bi) with an acid balogenide in, for example, benzene or toluene, in the presence of an alkaline earth metal carbonate or alkali metal carbonate. The reaction temperature is between C and 2 ° C.

The carboxyl protecting groups X and the hydroxyl protecting groups which may be used in the reactions described above may be the conventional protecting groups used in penemochemistry (see, e.g., European Patent Application Publication No. 0013662). Preferred carboxyl protecting groups are allyl groups, e.g. The preferred hydroxyl protecting group is trichloroethoxycarbonyl.

Other suitable hydroxyl protecting groups are, for example, benzyloxycarbonyl, ρ-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl and allyloxycarbonyl.

Other suitable carboxyl protecting groups include benzyl, p-nitrobenzyl, and benzhydryl.

Removal of the hydroxyl protecting group at the 8-position is known in penem chemistry. The preferred protecting group (trichloroethoxycarbonyl) can be removed with zinc in acetic acid.

Similarly, the carboxyl protecting groups can be removed by conventional methods. Preferred X groups) are most conveniently removed as described in European Patent Application Publication No. 0013663.

Thus, the alb groups are preferably in a suitable aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride, potassium or sodium 2-ethylhexanoate or 2-ethylhexanoic acid, and a palladium compound and a triarylphosphine compound such as triphenyl -phosphine mixture was removed as a catalyst.

Removal of the allyl protecting group with hexanoic acid affords a compound of formula I wherein R is hydrogen; when sodium or potassium hexanoate is used, a compound of formula I is obtained wherein R is sodium or potassium.

Other pharmaceutically acceptable salts of the compound of Formula I may be prepared from the sodium or potassium salt by known methods, for example by ion-exchange of the sodium salt in aqueous solution. Similarly, the pivaloyloxymethyl ester of the compounds of Formula I may be prepared from the sodium or potassium salt in a known manner.

The compounds of the invention are active against gram-positive and gram-negative bacteria. Most importantly, they are orally active antibacterial agents, which allow good blood levels to be achieved when using antibacterial doses. The compounds of the present invention are active against Gram-positive organisms such as Staphylococcus epidermidis and Bacillus subtilis and against Gram-negative organisms such as E.coli and Salmonella in a concentration of 0.1 to 100 pg / ml according to standard microbiological assays. In addition, they act on organisms that produce beta-lactamases such as penicillanase and cephalosporinase, and thus are resistant to these enzymes. For example, sodium N, R, 6S.8R / -6- (1-hydroxyethyl) -2- (2-fluoroethylthio) penem-3-carboxylate and the corresponding potassium salt versus Staphylococcus 7607010 At a concentration of 0.5 µg / ml, it is effective against B. subtilis 11 19601, a beta-lactamase producing organism at a concentration of 0.06 k® ml.

The invention also relates to the preparation of such pharmaceutical compositions. comprising an antibacterially effective amount of a penile compound of formula I in association with a pharmaceutically acceptable carrier or coating. The compounds of formula I may be the only antibacterial component of the pharmaceutical composition or may be mixed with other antibacterial and antifungal agents

-3190 044 or enzyme inhibitors.

Oral pharmaceutical compositions are preferred. Particularly preferred is a pharmaceutical composition which is an oral antibacterial dosage unit and a compound of formula I, particularly wherein R is sodium or potassium. for example, an antibacterially effective amount of sodium (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-fluoroethylthio) penem-3-carboxylate together with a pharmaceutically acceptable carrier. Of these compositions, solids are particularly useful. Oral dosage forms are characterized by an unusual combination of high or sustained action, broad antibacterial spectrum, and efficacy in oral administration.

The dosage of the penem compounds of the invention will depend on the age and weight of the animal being treated, the mode of administration and the severity and type of bacterial infection to be prevented or treated. Generally, the daily dose will be in the range of 5 to 200 mg / kg / day, preferably 20 to 80 mg / kg / day.

The compounds of the invention may be formulated for oral administration in the form of tablets, capsules, elixirs or the like. Similarly, they can be mixed with animal feed. They are topically used in the form of hydrophobic and hydrophilic ointments, aqueous, non-aqueous or emulsion-type milks or creams.

The compounds of Formula I may be administered in liquid form such as solutions, suspensions, and the like for the treatment of ears and eyes, and may be administered parenterally by intramuscular injection.

Examples of compounds of the invention include:

1. sodium or potassium (5R, 6S, 8R) -2- (2'-fluoroethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

2. Sodium or potassium (5R, 6S, 8R) -2- (3'-fluoropropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

3. sodium or potassium (5R, 6S, 8R, -2-, 2'-fluoropropylthio) -6- (1-hydroxyethyl) penemcarboxylate;

4. Sodium or potassium (5R, 6S, 8R) -2- (1-fluoromethylethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

5. Sodium or potassium (5R, 6S, 8R, -2-, 1-fluoromethylpropylthio) -1-hydroxyethyl / penem-3-carboxylate;

6. sodium or potassium (5R, 6S, 8R) -2- (2-fluoromethylpropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

7. sodium or potassium (5R, 6S, 8R / -2- / 2 ', 2', 2'-trifluoroethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

the free acids and their pivaloyloxymethyl esters and the 5R, 6R, 8S / isomers of the aforementioned acids, salts and esters.

The following examples illustrate the process of the invention.

. example. 17 _l '3S, 4R, 5Rf-331-trichlorethylene butoxycarbonyl> - <> xi ethyl / -4- / 2-hydroxyethyl-thiocarbonyl thio ltio / -a: azetidine-2-one g! Methyl (5R, 6S, 8R) -2,2-dimethyl-6- (1-trichloroethoxycarbonyloxyethyl) penam-3-carboxylate was dissolved in 150 mL of methylene chloride at 0-5 ° C, 7.36 mL sulfuryl chloride was added and stirred for 1 hour at room temperature. The reaction mixture was poured into an aqueous solution of sodium bicarbonate in excess with stirring. The liquid phases are separated, the agent phase is dried and evaporated. The residue was dissolved in 100 ml of Nethylene chloride and treated with ozone until blue at -78 ° C; Dimethyl sulfide (5 mL) was added to the reaction mixture at room temperature and stirred for 1 hour, followed by a mixture of 10 mL of beta-mercapto-ethanol and 6 g of potassium hydroxide in 200 mL of 50% aqueous ethanol cooled to 0 ° C. ml of carbon trisocarbonate solution in carbon disulfide. The chloro-lactam solution was also reacted with trithiocarbonate solution at 0 ° C for 45 minutes with stirring and then diluted with water. The reaction mixture was extracted with methylene chloride, washed with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 30% diethyl ether in methylene chloride. The same fractions containing the title compound, which were analyzed by thin layer chromatography, were concentrated and the product was obtained as a light yellow oil.

Yield: 8.1 g

Infrared (CH, CL) 3550, 1770, 1750

-1 to ~ cm

3) 3S, 4R, 5R, -3-β-Trichloroethoxycarbonyloxyethyl-4- (2-tert-butyldimethylsilyloxy) ethylthiocarbothioylthio-azetidine- 2-one

The product obtained in Step A (7.07 g) was dissolved in a mixture of methylene chloride (50 ml) and pridine (1.43 ml), tert-butyl chlorodimethylsilane (2.64 g) and imidazole (0.1 g). The solution was stirred at room temperature for two days, washed with water and evaporated to dryness. The residue was chromatographed on silica gel, eluting first with dichloromethane / hexane and then with increasing volumes of diethyl ether in methylene chloride. The fractions containing the title compound, after TLC analysis, were combined, evaporated to give the title compound as a light yellow oil.

Yield: 8.4 g.

Infrared spectra: 3400.1700 and 1750 cm -1.

C) N- (5R, 6S, 8R / -242- tert-Butyldimethylsiloxy (ethylthio) -6- (1-trichloroethoxycarbonyloxyethyl) penem-3- carboxylate

8.4 g of the product obtained in Step B) are dissolved in 50 ml of methylene chloride containing 2.69 g of allyloxalyl chloride and stirred at 0-5 ° C, while 2.32 g

A solution of diisopropylethylamine in -4190 044 in methylene chloride (15 mL) was added dropwise. The reaction mixture was stirred for a further half an hour at 0 to 5 ° C, washed with water, diluted with hydrochloric acid and then aqueous sodium bicarbonate was added. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue is dissolved in 100 ml of ethanol-free chloroform, 1.0 g of calcium carbonate is added and the mixture is refluxed and 5 g of triethyl phosphite are added with ca. In 3 hours. The mixture was refluxed for a further 18 hours, cooled, chromatographed on silica gel eluting with a mixture of methylene chloride and hexane, methylene chloride and finally 1% diethyl ether in methylene chloride. The fractions containing the title compound were combined after TLC to give the title product as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 0.10 (s, 6), 0.92 (s, 9), 1.54 (d, 3, J = 7, 3.07 (m, 2), 3.84 (m, 3), 4.76 (m, 2), 4.79 (s, 2), 5.1-5.6 (m, 3), 5.64 (d, 1, J = 2.5 ) and

5.7-6.2 (ni, 1).

D) Allyl-5R, 6S, 8R (-2- (2-hydroxyethylthio) -6- (1-trichloroethoxy) carboxy] -ethyl / penem-3-carboxylate

The product obtained in Step C (4.46 g) was dissolved in a mixture of tetrahydrofuran (32 ml), water (4 ml) and acetic acid (4 ml). The solution was stirred for 18 hours at room temperature with 2.4 g of tetra-n-butylammonium fluoride. The reaction mixture was poured into a two-phase solvent system consisting of methylene chloride and water with stirring. The organic layer was washed with aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed on silica gel, eluting with a mixture of ethyl ether and methylene chloride. The fractions containing the title compound, after TLC analysis, were combined and evaporated to give the title compound as a yellowish oil.

Yield: 2.9 g

Nuclear Magnetic Resonance Spectrum (CDC13): 1.49 (d, 3.J = 7), 2.17 (m, 1, interchangeable with D, O), 3.12 (m, 2), 3.70- 4.0 (m, 3), 4.72 (m, 2), 4.76 (s, 2), 5.1-5.6 (m, 3), 5.67 (d, 2, J = = 2.5) and 5.7-6.2 (m, 1).

E) Allyl (5R, 6S, 8R) -2- (2-Fluoroethylthio) -6- (trichloroethoxycarbonyloxyethyl) penem-3-carboxylate

400 mg of the product obtained in D) are dissolved in 25 ml of methylene chloride and 1 g of calcium carbonate is added at -78 ° C. Diethylamino sulfur trifluoride (0.35 mL) was added and the mixture was stirred for 1/2 hour. The mixture was diluted with ethyl acetate: stirred with water at 0 ° C for five minutes. The layers were separated and the organic layer was washed with water and evaporated to dryness. The residue was chromatographed on silica gel. ethyl ether / methylene chloride as eluent. Fractions containing the same products were combined after TLC and evaporated to give the title product.

Yield: 200 mg.

Nuclear Magnetic Resonance Spectrum: 6.2-5.8 (1H, m); 5.7 (1H, d, J = 1 cps); 5.5-5.3 (3H); 4.85 (1H, J = 6 cps and 50 cps); (F-CH coupling); 3.95 (1H, d, d, J = cps and 9 cps);

3.25 (tt / _S-CH2 /); 1.4 (3H, d, J = 9 cps).

IR: 1795, 1765 and 1695 ^cm-first

F, Allyl (5R, 6S, 8R) -2- (2-Fluoroethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate

200 mg of the product of Step E are dissolved in 10 ml of tetrahydrofuran. 300 mg of zinc, 0.5 ml of acetic acid and 0.5 ml of water are added. The mixture was stirred at -5 to 0 ° C for 1.5 hours. Triturate with ethyl acetate, remove the extract with aqueous calcium carbonate, and filter. The ethyl acetate solution was evaporated to dryness and chromatographed on a silica gel column, eluting with 10% ethyl acetate in methylene chloride. The TLC fractions containing the same material were combined, evaporated to give the title product.

Yield: 100 mg.

Nuclear Magnetic Resonance Spectrum: 6.2-5.8 (1H, m), 5.7 (1H, d, J = 1.5 cps), 5.5-5.3 (2H; 1H, J = 7 and 50 cps), 4.35 (1H, t, J = 50 cps), 3.75 (1H, dd, J = 1.5 and 9 cps); 3.3 (2 H, m),

1.1 (3H, d, J = 9 cps).

IR: 3400, 1795, 1720, 1695 cm ^-1 .

G) Sodium (5R, 6S, 8R) -2- (2-fluoroethylthio) -6- (1-hydroxyethyl) -perem -3-carboxylate mg of the product obtained in Step F is dissolved in 10 ml of methylene chloride. 48 mg of sodium hexanoate, 28 mg of tetrakis (triphenylphosphine) palladium and 30 mg of triphenylphosphine are added. The reaction mixture was stirred under nitrogen for half an hour. The methylene chloride was extracted with water; Key in. The layers are separated. The organic layer was diluted with ethyl acetate, washed with water, and the aqueous layer was treated with 8 mg of sodium bicarbonate, combined with the aqueous layer obtained previously and lyophilized. The PC is not salt was dissolved in 3.0 mL water, and passed through C ₁₈ Kovrig savgélen under pressure, and then washed with water. The aqueous eluate was lyophilized to give the title compound.

Yield: 30 mg. Buff - 150.8 ° (H, O)

Nuclear Magnetic Resonance Spectrum (D ₂ O): 5.75 (1H, d, J = 1 cps);

5.35 and 4.4 (2t, -CHyF, 2H, J = 1.8 cps, 9 cps); 4.3 (1H, m); 3.95 (1H, dd, J = 1 and 0 cps); 3.3 (2 H, m); 2.2 (1H, deuterated OH); 1.3 (3H, d, J = 9 cps).

Similarly, in Example 1, Step G, sodium hexanoate is replaced with an equivalent amount of hexanoic acid. the corresponding penem carboxylic acid is obtained, i.e.? (5R, 6S, 8R) -2- (2-Fluoroethylthio) -6- (1-hydroxyethyl) pentyl-3-carboxylic acid.

Other pharmaceutically acceptable alkali metal salts, such as the potassium salt, may be prepared from the sodium salt in a known manner, for example by ion-exchange of the sodium salt in aqueous solution. or from a base of penem carboxylic acid containing the corresponding cathi-5190 044 ontes. In each case, the pharmaceutically acceptable salt is isolated by lyophilization. Suitable metabolizable phthalidyl and pivaloyloxymethyl esters can be prepared as described in Example 2 of European Patent Application Publication No. 13,662, e.g. in its presence.

Similarly, starting from the appropriate intermediates, the following compounds may be prepared:

Sodium or potassium (5R, 6S, 8R) -2- (3-fluoropropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate:

sodium or potassium (5R, 6S, 8R) -2- (2-fluoropropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (1-fluoromethylethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (1'-fluoromethylpropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (2-fluoromethylpropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate; and the corresponding free acids and pivaloyloxymethyl esters.

As stated previously, the compounds of the present invention are effective against both Gram-positive and Gram-negative bacterial strains, including anaerobic strains. Figures 2-8. Examples 3 to 9 show some dosage forms in which the compounds of the invention may be administered. In these formulations, the term "active ingredient" is used to mean (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-fluoroethylthio) penem-3-carboxylic acid or (5R, 6S) , 8R) -6- (1-Hydroxyethyl) -2- (3-fluoro-n-propylthio) -3-carboxylic acid or the equivalent of 3-carboxylic acid or pivaloyloxymethyl ester amount.

However, it is likewise appropriate to replace these compounds with an equally effective amount of the compounds listed above in the Examples.

Example 2

Injection preparation:

Per ampoule: Active substance (sterile powder).

Dosage units may be, for example, 125 mg, 250 mg, 500 mg, 1 g, 2 g.

U. sterile water for injection or U.S.P. Bacteriostatic water for injection according to FIG.

Example 3

Capsule mg / capsule mg / capsule

agent 250 500 microcrystalline cellulose 30 60 corn starch, dried 15 30 Silica gel 43 9 magnesium stearate 0.5 1 300.0 600.0

manufacture:

Components 1, 2, 3 and 4 are mixed in a suitable mixing vessel for 10-15 minutes. Add component 5 and stir for 1-3 minutes. The above mixture is filled into two-piece hard gelatin capsules of appropriate size.

Alternatively, components 1, 2, 3 and 4 may be stirred in a suitable mixing vessel for 10 to 15 minutes. Add half of component 5, mix for 1-3 minutes. The mixture is passed through a suitable compactor. The compacted mixture is passed through a suitable grinder equipped with a 16 mm mesh screen. The resulting material is stirred again, the other half of component 5 is added, and stirred for 1-3 minutes. The resulting mixture is filled into two size hard gelatin capsules of appropriate size.

Example 4

Tablet mg / tablet mg / tablet 1. active ingredient 250 mg 500 mg 2. microcrystalline cellulose 100 mg 200 mg 3. maize starch, dried 40 mg 80 mg 4. silica gel 6 mg 12 mg 5. magnesium stearate 4 mg 8 mg 400 mg 800 mg

manufacture:

Component 1, 3 is mixed with half of component 4 in a suitable mixer for 10 to 15 minutes. Half of component 5 is added and stirred for 1-3 minutes. The material is passed through a suitable compactor (or dry granulated on a 1-inch flat-bevel rotary tabletting machine). The compacted material or granules are ground in a suitable mill with a 16 mm mesh screen. The ground meal is mixed and component 2 and a are added

Remaining component 4. Stir for 10-15 minutes. Then half of component 5 is added and stirred for 1-3 minutes. The mixture is compressed into tablets of desired size and shape on a rotary tabletting machine. The tablets may also be coated by a standard coating process.

Example 5

Topical preparation:

Active ingredient 1. 25 mg / g

2. 400 mg / g ethyl alcohol

3. Hydroxypropylcellulose 15 mg / g

4. polyethylene glycol 400-560 mg / g

Components 1, 2 and 4 are mixed in a suitable mixer. With vigorous stirring, Comm

-6190 044 ponens are also added. Stirring is continued until a uniform mixture is obtained.

Example 6

Oral powder to be dissolved (I)

A) Powder preparation mg / g 1. active ingredient 463 Taste 2 q / s. 3. coloring agent q / s. 4. preservative q / s. 5. buffer material q / s. 6. saccharin 283

Total: 1.0 q

Components 1, 2, 3, 4 and 5 are thoroughly mixed, then component 6 is added and mixing is continued until a homogeneous mixture is obtained.

B) Dissolve 100 g of the above powder formulation in water in a graduated flask. 5 ml of this solution (1 teaspoon) contains 125 mg of active ingredient.

Example 7

Oral liquid mg / ml 1. active ingredient 25.0 2. sweetener qs Issue 3 qs 4. coloring agent qs 5. vegetable oil qs Altogether: 1.0 ml

90% of component 5 is poured into a suitable vessel. Add components 1, 2, 3 and 4 and mix well. The remaining component 5 is added to the final volume.

Example 8

Suppository weight

Active ingredient 1 125.0

2. Witepsol H-15 1868

Component 2 is thawed and mixed with component 1 until a homogeneous mixture is obtained. Pour into mold and freeze in refrigerator and remove from mold.

Example 9

N, 3R, 6S, 8R) -6- (1-Hydroxyethyl) -2- (2'-fluoro-ethylthio) -penem-3-carboxylate

A) 0.654 g of (3S, 4R, 5R) -3- [1- (2,2 ', 2'-trichloroethoxy) carbonyloxyethyl] -A- (2-fluoroethylthio) carbonate A solution of thioylthio (-azetidin-2-one in 6 ml of methylene chloride) was cooled to 10 ° C and 0.6 g of calcium carbonate was added with stirring followed by 0.263 g (1.2 equivalents) of allyloxalyl chloride. A solution of diisopropylethylamine (0.32 mL, 1.2 equiv.) In methylene chloride (1 mL) was added dropwise over 5 minutes at about 10 ° C.

After about 1 minute, when no starting material can be detected by TLC (about 15 ° C), the material is transferred to a separatory funnel with alcohol-free chloroform. Wash twice with ice water, remove the calcium carbonate by filtration, dry over anhydrous sodium sulfate, and transfer the solution to a 100 mL three neck flask. Its volume with chloroform is ca. Make up to 50 ml and add 0.6 ml (2 equivalents) of triethyl phosphite in 20 ml of chloroform at reflux over 3 hours. The mixture was refluxed for an additional 18 hours, evaporated and chromatographed on 14 g of silica gel eluting with 25% ether in hexane. After combining and evaporating the appropriate fractions, 420 mg of allyl-5R, 6S, 8R (-6-) 1-trichloroethoxycarbonyloxyethyl (-2-) 2-fluoroethylthio / -2-penem-3-carboxylate (58%). Recrystallization from ether-hexane gave the above allyl ester in crystalline form. Yield: 330 mg (46%).

B) The product of Step A is further converted according to Example 1, Steps F and G to give the title compound.

Similarly, using the appropriate starting materials, the following compounds may be prepared:

sodium or potassium (5R, 6S, 8R) -2- (3'-fluoropropylthio) -6-1-hydroxyethyl / penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) - (2-fluoropropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (1'-fluoromethylethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (1-fluoromethylpropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (2-fluoromethylpropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium cut potassium (5R, 6S, 8R) -2- (2 ', 2', 2-trifluoroethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate and the corresponding acids free and pivaloyloxymethyl esters

They can be prepared as described in the last part of Example 1.

Example 10 (5R.bS.SR) -6- (1-Hydroxyethyl) -2- (2,2,2-trifluoroethylthioethyl) -3-carboxylate

A) Allyl- (5R, 6S, 8R) -6- (1-Hydroxy-ethyl) -2-thion-penam-7-1

The equilibrium mixture of -3-carboxylate and allyl- (5R, 6S, 8R) -6- (1-hydroxyethyl) -2-thiolpentem-3-carboxylate is ca. 250 mg are dissolved in 3 ml of tetrahydrofuran. 1.5 equivalents of 2.2.2-trifluoroethyl trifluoromethanesulfonate (CF ₃ SO-, CH ₇ CF ₃ ) are added followed by 1 equiv. Of powdered potassium carbonate and two hours at room temperature. The reaction mixture was filtered and washed with methylene chloride containing 27 phosphoric acids. The methylene chloride phase was evaporated to give a semi-crystalline residue. This residue was dissolved in a 50:50 (v / v) warm mixture of trichloromethane and petroleum ether, cooled and the white crystals filtered off. Further cooling further crystallizes; the white crystals are filtered off. The mother liquor was loaded onto a silica gel column, eluted with a 95: 5 mixture of methylene chloride and ethyl acetate. After combining and evaporating the appropriate fractions, pure allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2 ', 2', 2'-trifluoroethylthio) -penem-3 160 mg of carboxylate are obtained.

B) The 160 mg allyl ester obtained in Step A is dissolved in 2 ml of methylene chloride. Approx. 50 mg triphenyl phosphite followed by 4 equivalents of 1 M pyridinium formate containing 10% excess pyridine. To the reaction mixture was added portionwise 250 ml of triphenylphosphine palladium (0) saturated methylene chloride. The reaction was completed in 3 hours. The reaction mixture was washed with 2% aqueous phosphoric acid.

The phosphoric acid solution (pH 1) was extracted four times with ethyl acetate and evaporated to give (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2 ', 2', 2-trifluoromethyl) 59 mg. ethyl thio) penem-3-carboxylic acid is obtained.

C) The free acid is dissolved in 5 ml of a 50:50 mixture of tetrahydrofuran and water and 1 equivalent of sodium bicarbonate is also dissolved in a 50:50 mixture of tetrahydrofuran and water. The mixture is lyophilized to give (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2 ', 2', 2'-trifluoroethylthio) penem-3-carboxylate.

In a similar manner, starting from the appropriate intermediates, the following compounds can be prepared:

sodium or potassium (5R, 6S, 8R) -2- (3-fluoropropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (2-fluoropropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (1'-fluoromethyl-ethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (1-fluoromethylpropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (2-fluoromethylpropylthio) -6- (1-hydroxyethyl) penem-3-carboxylate;

sodium or potassium (5R, 6S, 8R) -2- (2-fluoroethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate; and the corresponding free acids and pivaloyloxymethyl esters.

Example 11

Preparation of a solution of Aj CFjSOjClfCFj

Under nitrogen, 0.735 mL of pyridine was dissolved in 25 mL of dichloromethane. The flask was cooled to minus 20 ° C and 1.45 mL (CE3SO4), O was added slowly. To the solution was added 0.703 ml of 2,2,2-trifluoro-1-hydroxyethane and the reaction mixture was warmed to room temperature. The reaction mixture was filtered and dichloromethane was distilled off. The product is co-distilled with dichloromethane. The distilled solution is used as starting material in Step B. Nuclear Magnetic Resonance Spectrum: 4.40 ppm (O-J = 8 cps).

B) Allyl (5R, 6S, 8R) -6- (1-Hydroxymethyl) -2- (2 ', 2', 2'-Trifluoroethylthio) penem-3-carboxylate

250 mg of the allyl-protected tautomeric mixture of IIa and IIIb are dissolved in 3 ml of tetrahydrofuran and 5 ml of CF ₃ SO ₃ CH, CF ₃ solution obtained in Step A) are added. To the mixture was added 1 equivalent of powdered potassium carbonate and stirred for 3.5 hours. The reaction mixture was filtered and the residue was washed with dichloromethane containing 2% phosphoric acid. Evaporation of the solvent gives rise to crystals. The crystals were chloroform / petroleum ether 1: 1 v / v. and then cooled and the precipitated crystals were collected. This operation is repeated. The mother liquor was chromatographed on a silica gel column. Yield: 168 mg of the title compound.

Nuclear Magnetic Resonance Spectrum (EM 390, 90 mHz, PMR in chloroform): 1.35 ppm (D, J = 6 ops, 3H), 2.50 ppm (bs), 3.50 ppm (dd, J = 5 and 9 cps) , 2H), 3.75 ppm (dd, J = 6 and 1 cps, 1H), 4.20 ppm (m, 1H), 4.65 ppm (m, 2H), 5.1-5.43 ppm ( m, 2H), 5.6 cpm (d, J = 1 cps, 1H), 5.6-6.2 ppm (m, 1H).

C) (5R, 6S, 8R) -6- (1-Hydroxyethyl) -2- (2 ', 2', 2'-trifluoroethyl) penem-3-carboxylic acid

160 mg of the product of Step B are dissolved in 2 ml of dichloromethane. To the solution is added 50 mg of triphenylphosphine. 4 equivalents of 1 M pyridinium formate (10% excess pyridinium) are then added. A total of 250 µl of triphenylphosphene-palladium catalyst was added. The reaction is complete within 3 hours. The reaction mixture was washed twice with 2% phosphoric acid. The phosphoric acid solution was extracted 4 times with ethyl acetate. Part of the phosphoric acid solution was lost during the experiment and therefore the yield was low. After evaporation of the solvent, 54 mg of the title compound are obtained. The product was further purified by washing with dichloromethane / phosphoric acid. It is then dissolved in 5 ml of a mixture of tetrahydrofuran and water in the presence of 1 equivalent of sodium bicarbonate. The solution is then freeze-dried.

Mass Spectrum: M + 1 = 329.

Example 12

Pivaloyloxymethyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2'-fluoroethylthio) penem-3-carboxylate

100 mg of (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-fluoroethyl)

-8190 044

To a solution of the sodium salt of thio) -penem-3-carboxylic acid in 2 ml of dimethylformamide was added 0.07 ml of chloromethyl pivalate and stirred at room temperature for 20 hours. TLC (25% ethyl acetate / dichloromethane) indicated non-polar precipitation. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL). The dichloromethane extract was extracted with water (10 mL). The organic layer was dried over sodium sulfate and evaporated to give an amber oil. The thin-layer chromatogram shows the spot characteristic of the main product. The IR and NMR spectra are consistent with the desired structure.

Infrared 3400, 1795, 1755, 1700 cm- ¹ NMR (δ, ppm): 5.9 (q, 2H), 5.7 (1H, d, J = 1.5 cps), 4.9 and 4.4 (2H, tt, -CH, F, J = 6 and 45 cps),

4.25 (m, 1H), 3.8 (dd, 1H, J = 1.5 and 6 cps), 3.5 and 3.2 (2H, tt, J = 6 and 20 cps), 1.35 (3H, d, J = 6 cps), 1 (2 (s, 9H).

Sodium (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2'-fluoroethylthio) penem- was found to be antibacterial on Müller-Hinton agar at pH 7. 3-Carboxylate inhibited the growth of the bacteria listed in Table I at the following minimum inhibitory concentration (pg / ml).

Table I micro-organisms MIC micro-organisms MIC organism organism Acinetobacter 79043017 0.1250 77080902 0125 80080408 0.2500 79121104 2000 79111505 0.1250 77080901 0.5000 75082817 0.1250 77080954 20000 80103108 0.2500 75091623 1.0000 80100203 1.0000 77041312 1.0000 77081847 0.2500 79062004 0.2500 79121126 0.2500 78120401 0.5000 75041104 0.2500 80070723 0.1250 77062904 0.1250 77080952 1.0000 80080412 0.1250 77062909 2.0000 80080445 0.2500 76042103 0.1250 77080906 0.2500 79040613 0.1250 Citrobacter 79112613 0.5000 76022001 0.2500 79030103 0.2500 79012521 0.1250 80103101 0.5000 79012543 0.1250 76050403 0.2500 76041201 0.2500 E. coli 77081846 0.2500 79121101 0.1250 75041106 0.2500 75020706 0.5000 77080949 0.2500 001574-1 0.2500 80102913 0.2500 79101902 0.2500 77080903 0.5000 80091808 1.0000 79121109 0.1250 Enterobacter 80091813 0.2500 79101907 0.2500 79012503 0.2500 72012502 0.5000 80091812 0.5000 76052901 0.1250 10

micro-organisms organism MIC micro-organisms organism MIC 77381832 0.2500 78022362 0.2500 77081804A 0.2500 77081828 1.0000 79062510 0.2500 77081828 1.0000 75040605 0.1250 75081106 1.0000 75043005 0.2500 80060602 0.5000 79070501 1.0000 80090860 2.0000 80103104 0.2500 80092501 1.0000 71012503 2.0000 71030901 1.0000 Pro teus / 75043003 0.2500 Providence 78111402 0.5000 770020403 .2500 77080959 0.5000 77020404 .2500 77061306 0.2500 77020402 .2500 17081802 0.5000 75082803 78071009 .5000 .5000 Klebsiella 77080960 .2500 76040112 0.1250 79043018 .2500 76031502 0.1250 74052806 1.0000 78100504 0.2500 77051703 1.0000 80020801 0.1250 78031573 .5000 74041603 0.2500 76090707 .5000 75032102 0.1250 78120402 1.0000 79111503 0.2500 79082802 1.0000 80020809 0.2500 78071017 .5000 80102909 0.2500 72012521 1.0000 79100201 0.1250 78040601 1.0000 76082701 0.2500 72052304 4.0000 80090882 80103112 1.0000 0.2500 78071014 1.0000 80103115 0.2500 Proc. stuartii 74120401 0.2500 Salmonella 80020810 0.2500 -Shigella 74111801A 0.5000 Morganella 0C2 NEWPT 0.1250 75091615A 1.0000 76061713 0.1250 77020408 1.0000 00013313 0.2500 77081842 0.5000 OGRGCUBA 0.2500 80082106 1.0000 77072001 0.2500 80090859 0.5000 79112610 0.2500 75051303 0.5000 77072002 0.5000 75082809 1.0000 76061707 0.2500 77080933 1.0000 76061716 0.2500 77080932 2.0000 74060311 0.2500 80090864 0.5000 79103101 0.5000 80103157 1.0000 77053109 0.1250 72012507 1.0000 80082103 0.2500 76120901 1.0000 76061701 0.2500 79040664 2.0000 80081402 0.2500 80091806 1.0000 78101707 0.2500 77080934 0.5000 77062906 0.5000 Stapiiylo- 74050202 0.5000 coccits 80032105 0.5000 00000868 0.0625 80080423 0.2500 76070107 0.2500 77061304 1.0000 000SG5I1 0.0625 80081203A 0.1250 78011916 0.2500 72012501 4.0000 00000211 0.0625

-9190 044

micro-organisms organism MIC micro-organisms organism MIC 78053002 00 625 80090887 0.2500 00000835 0.1250 80090888 0.2500 78100502 0.0625 80090889 0.1250 79011101 0.1250 00027626 64.0000 00000226 0.1250 72052308 0.1250 Streptomyces 76070106 0.1250 coccus 76070103 0.5000 0969/72 16.0000 76070101 1.0000 Z 8.0000 76070104 1.0000 80030305B 4.0000 79021510 .2500 79101803B 16.0000 77072606 1.0000 79112608 8.0000 72052302 2.0000 80011006 .1250 Group D 80090894 2.0000 75100802 .5000 79112502B 16.0000 77072603 1.0000 WOOD 8.0000 79013132 .5000 78091823A 16.0000 77072718 2.0000 78091813A 16.0000 80090865 .1250 78040654A 16.0000 75100801 1.0000 78091822D 16.0000 80020808 4.0000 ATCC29212 80090880 2.0000 79082202 1.0000 80091805 2.0000 72012524 1.0000 79060504 .5000 Serratia 76091606 2.0000 77080972 .2500 76032305 4.0000 79121123 .5000 78080424 2.0000 75082819 4.0000 75042113 8.0000 80103103 .2500 77012512 2.0000 75012721 1.0000 80022917 8.0000 74041505 1.0000 74011803 8.0000 79030102 1.0000 80090809 16.0000 79030606 .5000 80090867 8.0000 75082815 1.0000 80103122 1.0000 79121114 4.0000 77080914 4.0000 Proteus 77072705 1.0000 mirabilis 76062203 1.0000 78031559 1.0000 75032101 8.0000 78091110 2.0000 75041604 4.0000 79071204 1.0000 75042111 4.0000 78080422 1.0000 76081805 2.0000 79030912 0.5000 ' 74121201 1.0000 76072701 2.0000 79100302 1.0000 77080944 4.0000 76100703 0.1250 78031301 2.0000 76070102 1.0000 79050223 0.5000 77040102 0.0625 72012514 4.0000 80090204 0.1250 79013103 4.0000 77041308 0.0625 79013130 4.0000 76070110 1.0000 79050218 1.0000 78041902 64.0000 00012453 1.0000 77081817 64.0000 72012515 0.5000 78060814 2.0000 78022349 2.0000 78121401 0.2500 79110501A 0.1250 80090886 0.5000

micro-organisms organism MIC micro-organisms organism MIC Streptomyces Streptomyces coccus coccus 80060504 0.0625 C Works 0.0625 Sanders4 0.2500 C Thacker 0.0313 488-78 0.1250 G Parsons 0.0625 The Hamer 0.1250 viridans The G-F 0.0313 Sanders 2 0.0313 The Harper 0.0313 BL3848 0.1250 B Flame 0.1250 918-78 0.1250 B Petruzzlia 0.0625 1063-78 0.0625 B G-D 0.1250 516-78 0.1250

Claims

Claims (8)

Claims A process for the preparation of 2-fluoroalkylthio-substituted penem carboxylic acid derivatives of the formula I C2-C4 linear or branched fluoroalkyl having from 1 to 3 fluorine atoms on carbon at least one carbon atom separated from the 2-sulfur atom, and R is a hydrogen atom, a pharmaceutically acceptable cation or a pivaloyloxymethyl tube, and stereochemistry for the preparation of 5R, 6S, 8R or 5R, 6R, 8S - a) for the preparation of compounds of the formula I in which A represents a monofluoroalkyl group, a compound of the formula II, in which the configuration is a straight or branched C 2 -C 4 alkyl group represented by the formula I; substituted under fluorine atom by a Lg group, preferably a hydroxy group substituted by a fluorine atom, which is separated from the sulfur atom by 2 at least 2 carbon atoms, X is a carboxyl protecting group, preferably an allyl group and optionally an 8-hydroxy group of the penem molecule; fluorinated with ethoxycarbonyl; or b) a compound of formula III, in which the configuration given in formula I, X in process a) and the 8-position of the penem is optionally protected, preferably with trichloroethoxycarbonyl, by a compound of formula IV In this formula, G is a C 2 -C 4 linear or branched alkyl group and has 1 to 3 fluorine atoms on its carbon atom, which is separated by at least one carbon atom from the Y atom or group, and Y is a leaving group, preferably chlorine. -, bromine or iodine - alkylating, or c) a compound of formula X wherein the configuration is a 3S, 4R, 5R or 3R, 4R, 5S, A 'fluralkyl group which is a straight or branched chain and -10190 C 44 contains from 1 to 3 fluorine atoms on carbon at least one carbon atom separated from the sulfur atom, X is as defined above and optionally protected at the 5-position by a trivalent organic phosphorus compound and optionally protected by any of the penem derivatives obtained above (s) and the compounds are isolated as the free acid, pharmaceutically acceptable salt or pivaloyloxymethyl ester. (First date: November 24, 1982) Process (a) according to claim 1, characterized in that the fluorination of a compound of formula II in which the Lg group is a hydroxy group is carried out with diethylaminohydrogen trifluoride in a solvent without hydroxyl group at a substantially neutral pH. (Priority: 11/24/1982) 3. A process according to claim 1 or a process according to claim 2, which is sodium (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-fluoroethylthio) penem. 3-carboxylate characterized in that a) reacting a compound of formula II wherein Z is -CH ₂ -CH ₂ -L _g , wherein L is as defined in claim 1 and has the configuration &lt; 6S, 8R; b) reacting a compound of formula IV wherein G is -CH ₂ -CH ₂ -F with a compound of formula III wherein X is as defined in claim 1 and has the configuration 5R, 6S, 8R; c) reacting a compound of formula V wherein A'-CH ₂ -CH ₂ -F has the configuration 3S, 4R, 5R. (Priority: 11/24/1982) Process (b) or (c) according to claim 1, for (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2 ', 2', 2'-trifluoroethyl) penem- 3-carboxylic acid, characterized in that: b) reacting a compound of formula IV wherein G is 2,2,2-trifluoroethyl with a compound of formula III wherein X is as defined in claim 1 and has the configuration 5R.6S, 8R; c) reacting a compound of formula V wherein 'a 2,2,2-trifluoroethyl has the configuration 3S, 4R, 5R. (Priority: 11/24/1982) Any process according to claim 1 or the process according to claim 2 pivaloyloxymethyl- (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-fluoroethylthio) ) -penem-3-carboxylate, characterized in that a) reacting a compound of formula II wherein Z is -CH, -CH-, -L, wherein L e p is as defined in claim 1 and has the configuration 5R, 6S, 8R; b) a compound of formula IV wherein G is 2-fluoroethyl is a compound of general formula III Reacting a compound of Formula 5 wherein X is as defined in claim 1 and has the configuration 5R, 6S, 8R; c) reacting a compound of formula V wherein A 'is 2-fluoroethyl and its configuration is 3S, 4R, 5R and converting the resulting product to its pivaloyloxymethyl ester. (Priority: 11/24/1982) 6. Process for the preparation of 2-fluoroalkylthio-substituted penem carboxylic acid derivatives of the formula I in the formula 15 The 2-fluoroethyl group and R is a hydrogen atom, a pharmaceutically acceptable cation or pivaloyloxymethyl group and a stereochemistry of 5R, 6S, 8R20, characterized in that a compound of formula II, wherein Z is 2-hydroxyethyl, X is a carboxyl protecting group, preferably allyl and the 8-hydroxy group of the penem molecule are protected, preferably with a trichloroethoxycarbonyl group, and the stereochemistry with diethylamino sulfur trifluoride of formula I is deprotected and the resulting penem derivative is deprotected. and isolating the compound in the form of a free acid, a pharmaceutically acceptable salt or a pivaloyloxymethyl ester. (Priority: 30 November 25, 1981) 7. A process for the preparation of a penem derivative of the formula I, as defined in claim 1, wherein A and R and the configuration are as defined in claim 1. The active ingredient produced by the process of any one of claims 1 to 6 is processed together with the customary carrier, diluent, excipient and / or other excipients of the pharmaceutical compositions. (First date: November 24, 1982) 8. The method of claim 7, wherein the oral dosage unit is provided. (Priority: 11/24/1982) 9. A process for the preparation of a pharmaceutical composition comprising the penem derivative of the Formula I as defined in claim 6 and the configuration as claimed in claim 6, characterized in that the active ingredient produced by the process of claim 6 is formulated in a conventional carrier, diluent, - and / or other processing aids. (Priority: 25.11.1981)